3,5-Dimethyl-1-adamantanamine (hereinafter, also described as “memantine”) is a N-methyl-D-aspartate (hereinafter, also described as “NMDA”) antagonist, and is used as an Alzheimer-type dementia therapeutic substance. The antagonist acts as a non-competitive electric dependent antagonist having low affinity for an NMDA receptor. Specifically, the antagonist is isolated from the NMDA receptor for transient highly-concentrated glutamate caused by physiological neuron excitation, and influences neither normal neural transmission nor long-term potentiation (LTP) formation. However, the antagonist protectively acts on neuron excitotoxicity for continuous low-concentrated glutamate stimulation. The antagonist has an action mechanism different from that of an acetylcholinesterase inhibitor, and therefore can also be used in combination with donepezil. Thus, the antagonist may extend the possibilities of Alzheimer-type dementia medical treatment.
As a method for synthesizing the antagonist, for example, various methods have been proposed as follows.
Non Patent Document 1 discloses a method for synthesizing 1-acetamido-3,5-dimethyladamantane involving reacting 3,5-dimethyl-1-adamantanol with acetonitrile and trifluoroacetic acid.
Patent Document 1 discloses a method for synthesizing aminoadamantanes. The method comprises:    (a1) a step of brominating adamantanes to synthesize bromoadamantanes, and thereafter hydrolyzing the bromoadamantanes to synthesize and isolate adamantanols;    (a2) a step of converting the adamantanols into acetamidoadamantanes; and (a3) a step of deacetylating the acetamidoadamantanes to obtain the aminoadamantanes.
Patent Document 2 discloses a method involving reacting adamantanes with an organic nitrile compound, concentrated sulfuric acid, and a carbocation compound in an organic solvent to synthesize 1-amidoadamantanes.
Patent Document 3 discloses a method for synthesizing memantine hydrochloride in which a stirring property is improved by using an organic acid for a solvent. The method comprises: (b1) a step of reacting 1-halo-3,5-dimethyladamantane with nitrile and concentrated sulfuric acid in an organic acid; (b2) a step of adding water to a reaction solution obtained in step (b1) to obtain 1-acetamido-3,5-dimethyladamantane as a crystal; (b3) a step of reacting 1-acetamido-3,5-dimethyladamantane obtained in step (b2) with a base in an alcohol; and (b4) a step of subjecting a reaction solution obtained in step (b3) to extraction, and thereafter adding hydrochloric acid to the resultant to obtain the memantine hydrochloride through crystallization.
Patent Document 4 discloses a method for synthesizing memantine hydrochloride in one pot. The method comprises: (c1) a step of reacting 1,3-dimethyladamantane with acetonitrile and an acid to synthesize 1-acetamido-3,5-dimethyladamantane; (c2) a step of reacting 1-acetamido-3,5-dimethyladamantane synthesized in step (c1) with a base in an alcohol solvent without isolating 1-acetamido-3,5-dimethyladamantane, to synthesize memantine; (c3) a step of adding hydrochloric acid dissolved in an alcohol solvent to the memantine obtained in step (c2); and (c4) a step of adding an ester solvent to the solution of step (c3) to obtain the memantine hydrochloride.
Patent Document 5 discloses a method for synthesizing memantine hydrochloride in one pot. The method comprises: (d1) a step of reacting 1-halo-3,5-dimethyladamantane with phosphoric acid and nitrile; and (d2) a step of synthesizing the memantine hydrochloride without isolating 1-acetamido-3,5-dimethyladamantane obtained in step (d1).
Patent Document 6 discloses a method for synthesizing memantine in one pot. The method comprises: (e1) a step of reacting 1-bromoadamantanes with acetamide and an inorganic acid in a solvent; (e2) a step of extracting 1-acetamidoadamantanes obtained in step (e1) by using an organic solvent; and (e3) a step of adding a base and diethylene glycol to a solution obtained in step (e2) to react them, to thereby obtain the memantine.